Protein Mediators & Strategies for Inhibition
Neuronal Cell Death Induced by Ischemic and Hemorrhagic Strokes Commonly known as cerebral vascular events, strokes are a significant source of morbidity and mortality worldwide. Ischemic strokes account for approximately 80% of all strokes and are caused by obstructed arteries that deprive the brain of oxygen and other nutrients. In contrast, hemorrhagic strokes stem from ruptured blood vessels that increase intracranial pressure and reduce blood flow to the surrounding tissue. While the mechanisms of pathology differ between ischemic and hemorrhagic strokes, both induce neuronal cell death. 1,2 Depending on the area of the brain affected, neuronal death can either be fatal or can impair speech, vision, or other sensorimotor functions.
Neuronal death following ischemic stroke is primarily attributed to dysfunction in the homeostasis of glutamate. Under physiological conditions, glutamate acts as the primary excitatory neurotransmitter in the nervous system.3 The release of glutamate into the synaptic space stimulates glutamate receptors of the NMDA subtype, which causes an influx of calcium and sodium and depolarization of the postsynaptic neuron. NMDA receptors (NMDA R) revert to the inactive state as transporters sequester glutamate into cells. However, ischemia causes ATP levels to decrease as cellular respiration is compromised. Decreased ATP production impairs glutamate transporters, results in neuronal depolarization, and leads to an unregulated accumulation of glutamate in the synaptic cleft. Excess glutamate over-activates NMDAR causing an influx of calcium, the production of reactive nitrogen species (RNS), mitochondrial dysfunction, and the generation of reactive oxygen species (ROS), all of which contribute to cell death. A secondary mechanism underlying neuronal cell death is inflammation.4,5 The ROS and cytokines released by dying neurons activate microglia, which secrete ROS and other cytotoxic factors that exacerbate neuronal damage.6
Molecular Targets for the Prevention of Stroke-induced Neuronal Cell Death
Tissue-Plasminogen Activator (tPA), the main treatment for ischemic strokes, activates the clot dissolving enzyme Plasmin, which restores blood flow to ischemic areas of the brain.7 When administered within three hours of symptom onset, tPA improves neurological function in humans. However, it is also associated with an increased risk of intracerebral hemorrhage. The limitations of tPA treatment emphasize the need for new ischemic stroke therapies. Recently, several proteins that mediate ischemia-induced neuronal cell death have been identified as potential pharmacological targets for stroke therapy. For example, Ofengeim et al. recently demonstrated that cleavage of the anti-apoptotic protein Bcl-XL contributed to ischemia-induced apoptosis in a rat model.8 Neuronal cell death was reduced in transgenic mice expressing a cleavage-resistant form of Bcl-xL indicating that inhibition of Bcl-xL cleavage may have potential for stroke treatment. Recent reports indicate that the voltage-gated proton channel, Hv1 may be another pharmacological target for stroke treatment.9 Wu and colleagues showed that mice lacking Hv1 had lower stroke-induced infarct volumes relative to wild-type mice.9
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